Asthma is an extremely common disorder accounting for 1 to 3% of all office visits, 500,000 hospital admissions per year and more pediatric hospital admissions than any other single illness. Asthma is no longer simply viewed as reversible airway obstruction or irritable airways. Rather, it is viewed primarily as an inflammatory illness that has bronchial hyperreactivity and bronchospasm as a result. The asthmatic inflammation that underlies the disease can be addressed by therapy with anti-inflammatory agents such as glucocorticoids or by those agents that target the role of the leukotrienes in the inflammation process.
The leukotrienes are a family of eicosatetraenoic acids derived from arachidonic acid which exhibit a wide range of pharmacological and physiological activities including bronchoconstriction and proinflammatory activity. Arachidonic acid is cleaved from the cell membrane, and acted upon by a cascade of enzymes localized to the perinuclear membrane including 5-lipoxygenase (ALOX5) which forms an unstable epoxide LTC4, followed by the addition of glutathione by LTC4 Synthase (LTC4S) forming the intercellular LTC4. LTC4 is transported extracellularly, where an amino acid is sequentially cleaved to form cystinyl leukotrienes LTD4 and LTE4. The cystinyl leukotrienes LTD4 and LTE4 act through the CYS-LT1 receptor. Two classes of drugs exist to modulate this pathway, ALOX5 inhibitors and CYSLT1 receptor antagonists.
A polymorphism in the promoter region of the ALOX5 gene has been demonstrated to affect the transcription of this gene. In vitro, human cells containing other than 5 random repeats of the Sp-1 binding motif (GGGCGG) have diminished activity. It follows that patients with asthma that have a variant genotype would be less responsive to therapeutic intervention with agents modifying this pathway. Prior clinical trials with the ALOX5 inhibitor compound ABT-761 have determined that efficacy of the compound is affected by genotype (Drazen, J. M. et al Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genetics 22;168-170, 1999). Patients that were either homozygous for the wild type allele (5 tandem repeats of the Sp-1 motif) or heterozygous (5/any other number of tandem repeats) had similar efficacy. However, the patients that were homozygous for no wild type alleles (variants) had a greatly reduced response to the compound. See FIG. 1 (which graphs data provided in Drazen et al. (1999) at page 168, column 2, last paragraph, continuing to page 169). In FIG. 1, homozygous for the wild type allele is denoted 5,5; heterozygous the wild and variant alleles is denoted 5,X; and homozygous for variant alleles is denoted X,X.
There is a need for a method of determining whether a given asthma patient would or would not be a good candidate for treatment with a leukotriene pathway modulator. It is therefore a goal of the present invention to provide an association between optimum clinical outcome of pharmacologic therapy and the genotype of the individual population. It is another goal of the present invention to be able to stratify patient populations into those subsets that will respond to a given pharmacologic therapy more or less well relative to other pharmacologic therapies. Another goal of the present invention is to be able to predict a patient's response to a given pharmacologic therapy on the basis of that patient's genotype. An additional goal of the present invention is to provide for a commercial method of predicting patient responses to pharmacologic therapies. Yet another goal of the present invention is to provide a method of screening candidate drug compounds for future suitable administration to a patient or to a patient population, based upon the genotype of the patient or the population. This entails a method of screening candidate drug compounds for variations in a measurable phenotypic effect among genetic subpopulations of subjects with asthma.